Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C[NH:8][CH:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10]2)C=CC=CC=1.S1C=CC=C1.[H][H]>CO.[Pd]>[NH2:8][CH:9]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10]1
Reactant: CCOC(=O)N1CCCC(NCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: CCOC(=O)N1CCCC(N)CC1
Yield: 100 %

Procedure:
69.1 Parts of ethyl hexahydro-4-[(phenylmethyl)amino]-1H-azepine-1-carboxylate were hydrogenated in the prescence of a solution of thiophene in methanol at normal pressure and at room temperature with 4 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 46.9 parts (100%) of ethyl 4-aminohexahydro-1H-azepine-1-carboxylate as a residue (interm. 28).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:15][C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[CH2:16](N(CC)CC)[CH3:17].C(I)C.C(Cl)(Cl)[Cl:27]>>[ClH:27].[CH2:16]([N:12]1[CH2:13][CH2:14][C:8]2[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:15][C:9]=2[CH2:10][CH2:11]1)[CH3:17]
Reactant: CCOC(=O)c1cc2c(s1)CCNCC2
Reactant: CCN(CC)CC
Reactant: ClC(Cl)Cl
Solvent: CCI
Product: CCOC(=O)c1cc2c(s1)CCN(CC)CC2
Product: Cl
Reaction time: 2 h

Procedure:
6.9 gm (0.0306 mol) of ethyl-5,6,7,8-tetrahydro-4H-thieno[2.3-d]azepine-2-carboxylate were dissolved in 60 ml of chloroform and 4.6 gm=6.4 ml (0.046 mol) of triethylamine, and the solution was heated to boiling. 5.5 gm=2.85 ml (0.035 mol) of ethyl iodide, dissolved in 10 ml of chloroform, were slowly added dropwise while stirring, and the mixture was heated for 3 hours more. After this time, another 1.3 ml of triethylamine and 0.57 ml of ethyl iodide were added. After another 2 hours of boiling, the same compounds were added again in the same quantities. After a total of 7 hours of heating the reaction was finished. The reaction mixture was allowed to cool, and was then extracted three times with water and dried over sodium sulfate. After the chloroform phase had been concentrated by evaporation in a rotary evaporator, 8 gm of a brown oil remained. By dissolving the oil in acetone and mixing the solution with ethereal hydrochloric acid the hydrochloride was precipitated which was then suction-filtered off and recrystallized from isopropyl alcohol.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[C:13]([NH:18][C:19]3[C:28]4[CH2:27][CH2:26][NH:25][CH2:24][C:23]=4[CH:22]=[CH:21][N:20]=3)[CH:14]=[CH:15][C:16]=2[CH3:17])[N:2]=1.CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[C:13]([NH:18][C:19]3[C:28]4[CH2:27][CH2:26][N:25]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:24][C:23]=4[CH:22]=[CH:21][N:20]=3)[CH:14]=[CH:15][C:16]=2[CH3:17])[N:2]=1
Reactant: Cc1ccc(Nc2nccc3c2CCNC3)cc1-c1cc2ccccc2cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(Nc2nccc3c2CCN(S(C)(=O)=O)C3)cc1-c1cc2ccccc2cn1
Reaction time: 8 h

Procedure:
To a solution of N-(3-(isoquinolin-3-yl)-4-methylphenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine (37 mg, 0.1 mmol) in THF (2 mL) is added DIEA (26 mg, 0.2 mmol) and methylsulfonyl chloride (14 mg, 0.12 mmol) subsequently. The reaction mixture is stirred overnight. After removing solvent by rotary evaporation, the residue is purified by HPLC to afford N-(3-(isoquinolin-3-yl)-4-methylphenyl)-6-(methylsulfonyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine as a white solid. MS m/z 445.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.34 (s, 1H), 8.11 (d, 1H, J=8.0 Hz), 7.97 (d, 1H, J=7.6 Hz), 7.88-7.85 (m, 3H), 7.76-7.71 (m, 2H), 7.66-7.63 (m, 2H), 7.16 (d, 1H, J=8.4 Hz), 6.57 (d, 1H, J=5.2 Hz), 4.24 (s, 2H), 3.45 (t, 2H, J=6.0 Hz), 2.91 (s, 3H), 2.75 (t, 2H, J=6.0 Hz), 2.26 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:22]=[CH:21][N:20]=1)=[O:18].[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([CH2:25][O:26][Si:27]([C:30]([CH3:32])([CH3:33])[CH3:31])([CH3:29])[CH3:28])[CH:22]=[CH:21][N:20]=1)=[O:18])(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2cc(CO[Si](C)(C)C(C)(C)C)ccn2)c(N)c2ccc(Cl)cc21
Product: CC(=O)Nc1c(C(=O)c2cc(CO[Si](C)(C)C(C)(C)C)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-6-chloro-1-ethoxycarbonyl-2-[4-[(tert-butyldimethylsilyloxy)methyl]pyridine-2-carbonyl]indole (step 5) and acetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17]C)=O)=[C:10]3[CH2:9][C:8](=[O:19])[N:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1.[CH3:27][N-:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([N:28]([CH3:29])[CH3:27])=[O:17])=[C:10]3[CH2:9][C:8](=[O:19])[N:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:6]=2[CH:26]=1
Reactant: C[N-]C
Reactant: COC(=O)c1ncn2c1CC(=O)N(c1ccccc1)c1cc(Cl)ccc1-2
Product: CN(C)C(=O)c1ncn2c1CC(=O)N(c1ccccc1)c1cc(Cl)ccc1-2

Procedure:
As described in previous example, 8-chloro-4,6-dihydro-6-phenyl-5-oxo-5H-imidazo[1,5-a] [1,5]benzodiazepine-3-carboxylic acid, methyl ester was converted to the dimethylamide, mp. 255°-257°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])=[CH:24][NH:23][C:22]=1[CH:34]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:34][C:22]4[NH:23][CH:24]=[C:25]([C:26]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[O:27])[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1c(C(=O)N2CCOCC2)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2CCOCC2)c[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 32.3 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (66.7 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 39 mg (32%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.30 (br s, 1H, NH), 11.69 (br s, 1H, NH), 9.16 (br s, 1H), 8.31 (s, 1H), 7.72 (dd, J=2.8 & 6.7 Hz, 1H), 7.46 (d, J=2.8 Hz, 1H), 7.43 (m, 1H), 7.41 (s, 1H), 7.35 (t, J=9 Hz, 1H), 3.59 (m, 4H, 2×CH2), 3.51 (m, 4H, 2×CH2), 2.21 (s, 3H, CH3). MS 483 [M++1].
Reaction SMILES: C(=O)([O-])[O-].[Tl+2].[C:6]([O:10][C:11]([N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH3:21][Si:22]([CH3:44])([CH3:43])[CH2:23][CH2:24][O:25][CH2:26][O:27][CH2:28][C:29]1[N:34]=[C:33](OS(C(F)(F)F)(=O)=O)[CH:32]=[CH:31][CH:30]=1>C1C=CC=CC=1>[C:6]([O:10][C:11]([N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:28][O:27][CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:44])([CH3:43])[CH3:21])[N:34]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: C[Si](C)(C)CCOCOCc1cccc(OS(=O)(=O)C(F)(F)F)n1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Tl+2]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)n1cccc1-c1cccc(COCOCC[Si](C)(C)C)n1
Reaction time: 23 h
Yield: 93.6 %

Procedure:
9.68 g of thallium carbonate (20.6 mmol), 1 g of tetrakis(triphenylposphine)palladium (0.86 mmol) and 2.45 g of 1-tert-butoxycarbonylpyrrol-2-yl boronic acid (11.6 mmol) are added to a solution of 4 g of trifluoromethanesulfonic acid 6-(2-trimethylsilanyl-ethoxymethoxymethyl)pyridin-2-yl ester (10.3 mmol) and 40 ml of benzene degassed by bubbling of nitrogen. The mixture is stirred for 23 hours under an argon atmosphere. The insoluble matter is removed by filtration on celite and then the solution concentrated under vacuum. The title product is isolated by chromatography on a silica column (eluent: dichloromethane/ethyl acetate; 99:1). 3.90 g of a yellow oil are recovered.
Reaction SMILES: [H-].[Na+].S(Cl)(=O)(=O)N.O.[S:9](=[O:13])(=[O:12])([OH:11])[NH2:10].O[CH2:15][C@:16]1([O:25][CH2:24][C@@H:22]([OH:23])[C@@H:20]([OH:21])[C@@H:18]1[OH:19])[OH:17]>CN(C=O)C>[CH3:15][C:16]1([CH3:18])[O:21][C@@H:20]2[C@@H:22]([CH2:24][O:25][C@@:16]3([CH2:15][O:12][S:9]([NH2:10])(=[O:11])=[O:13])[O:17][C:22]([CH3:24])([CH3:20])[O:19][C@H:18]32)[O:23]1
Reactant: NS(=O)(=O)O
Reactant: OC[C@@]1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O
Agent: NS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(COS(N)(=O)=O)OC(C)(C)O[C@@H]23)O1
Reaction time: 1.5 h

Procedure:
To a cold solution (-4° C.) of 2,3:4,5-di-O-isopropylidene-β-fructopyranose (75 g, 0.29 mol) in DMF (725 ml) was added 50% oily sodium hydride (16.34 g, 0.34 mol as NaH). After stirring for 90 min, sulfamoyl chloride (54.9 g, 0.48 mol) was added and the stirring continued for an additional 3.5 hr at that temperature. The reaction mixture was poured into cold water and extracted with toluene. The organic layer was dried (Na2SO4) and the solvents removed under vacuum to give a syrup which crystallized immediately. Recrystallization from ethylacetate/hexane gave pure 2,3:4,5-bis-O-methylethylidene)-β-D-fructopyranose sulfamate, mp 125°-126° C.
Reaction SMILES: Cl.C[O:3][C:4]1[C:16]2[CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]3[CH2:12][NH:11][CH2:10][C:9]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[O:23][CH3:24].B(Br)(Br)Br.C[OH:30]>C(Cl)Cl>[CH:24]([OH:23])=[O:30].[OH:3][C:4]1[C:16]2[CH2:15][CH:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:13]3[CH2:12][NH:11][CH2:10][C:9]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:23]
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)C1=C2CNC1
Reactant: CO
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: O=CO
Product: Oc1ccc2c(c1O)CC(c1ccccc1)C1=C2CNC1
Temperature: 25 °C
Yield: 58 %

Procedure:
A suspension of 54.5 mg (0.159 mmol) of 6,7-dimethoxy-4-phenyl-2,3,4,5-tetrahydro-1H-benz[e]isoindole hydrochloride, from Step 6, in 2 mL of methylene chloride was cooled to -78° C. and 0.64 mL of a 1M solution of boron tribromide in methylene chloride was added. The reaction was warmed to ambient temperature for 1 h and cooled to -78° C. before 1 mL of methanol was added. After warming to ambient temperature for 1 h, the solvents were removed in vacuo. Additional methanol (5 mL) was added and removed in vacuo. The product was chromatographed on silica gel eluted with ethyl acetate/formic acid/water (18:1:1) to give 29.8 mg (58% yield) of the title compound as an off-white powder, m.p. 144° C.; MS DCI: 279 (M+H)+ ; 1H NMR (d6 -DMSO) δ: 2.95-3.15 (m, 2H), 3.6-3.9 (m, 3H), 4.1-4.3 (m, 2H), 6.43 (d, 1H, J=7.5 Hz), 6.62 (d, 1H, J=7.5 Hz), 7.1-7.3 (m, 5H), 8.3 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=O)[CH3:2].I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH:20]([NH:23][OH:24])([CH3:22])[CH3:21]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:23]([CH:20]([CH3:22])[CH3:21])[O-:24])[CH:9]=[CH:10][C:11]=1[O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:2]
Reactant: CC(C)NO
Reactant: CCOc1cc(C=O)ccc1O
Reactant: CCCCCCI
Product: CCCCCCOc1ccc(C=[N+]([O-])C(C)C)cc1OCC

Procedure:
The title compound was prepared according to the procedure described in Example 28 using 3-ethoxy-4-hydroxybenzaldehyde, 1-iodohexane and N-isopropylhydroxylamine. The title compound was isolated in 47.1% overall yield as a solid, m.p. 69.0° C.
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.[CH:12](O)=[O:13]>C1(C)C=CC=CC=1>[CH:12]([N:4]1[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:1][CH2:2][CH2:3]1)=[O:13]
Reactant: c1ccc2c(c1)CNCCS2
Reactant: O=CO
Solvent: Cc1ccccc1
Product: O=CN1CCSc2ccccc2C1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 2,3,4,5-tetrahydro-1,4-benzothiazepine (4.56 g), formic acid (20 ml) and toluene (60 ml) was heated under reflux at 90° C. for four hours and then at 120° C. for a further three hours. The solvent was removed from the mixture by evaporation at reduced pressure. Purification of the residue by flash chromatography using dichloromethane as eluent gave 4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from hexane. Yield 3.73 g (m.p. 84°-87° C.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH2:8]([N:11]=[C:12]=[O:13])[CH2:9][CH3:10]>>[CH2:8]([NH:11][C:12]([N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)=[O:13])[CH2:9][CH3:10]
Reactant: O=C1CCNCC1
Reactant: CCCN=C=O
Product: CCCNC(=O)N1CCC(=O)CC1

Procedure:
To piperid-4-one (11.8 g) was added n-propyl isocyanate in small portions at room temperature with stirring. After stirring 48 hr the solvent was removed in vacuo, and the residue was treated with diethyl ether, yielding (D.31) (19.1 g, 86%) as a pale yellow oil.
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([Br:11])[CH:5]=1)=O.ClC1C=CC=[C:15]([C:19]([O:21]O)=[O:20])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(OCC)C>[C:19]([O:21][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([Br:11])[CH:5]=1)(=[O:20])[CH3:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1ccc(F)c(Br)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)Oc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
A solution of 1.09 gm (5 mMol) 3-bromo-4-fluoroacetophenone and 3.45 gm (20 mMol) m-chloroperbenzoic acid (70%) in 15 mL dichloromethane was heated at reflux for 18 hours. An additional 3.45 gm m-chloroperbenzoic acid were added and reflux continued for about 12 hours. At this point an additional 1.4 gm m-chloroperbenzoic acid were added and reflux continued for 18 hours. The reaction mixture was cooled to room temperature and was then diluted with 50 mL diethyl ether. The resulting mixture was cooled to 0° C. and was then treated with 15 mL 20% aqueous sodium thiosulfate. The resulting slurry was stirred for about 1 hour and then the phases separated. The organic phase was washed sequentially with 3×20 mL 20% aqueous sodium thiosulfate followed by 3×20 mL saturated aqueous sodium chloride. The organic phase was then dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 10:1 hexane:diethyl ether. Fractions containing product were combined and concentrated under reduced pressure to provide 68% of the desired compound.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][N:7](C)[CH2:8]CNC.Cl[C:14]1[N:19]=[C:18]([CH:20]=[O:21])C=CC=1.CN(C)CCN(C)C.CI.[Cl-].[Na+]>CCCCCC.O1CCCC1>[CH3:4][C:3]1[C:18]([CH:20]=[O:21])=[N:19][C:14]([N:7]([CH3:8])[CH3:6])=[CH:1][CH:2]=1
Reactant: [Li]CCCC
Reactant: CNCCN(C)C
Reactant: O=Cc1cccc(Cl)n1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: Cc1ccc(N(C)C)nc1C=O
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
2.65 ml of a 1.6 M solution of n-butyllithium in hexane are introduced into a solution of 0.53 ml of N,N,N'-trimethylethylenediamine (4.24 mmol) and 10 ml of tetrahydrofuran cooled to -60° C. The solution is stirred for 15 minutes at -40° C. and then it is cooled to -70° C. and a solution of 0.50 g of 6-chloropyridine-2-carbaldehyde (3.53 mmol) and 4 ml of tetrahydrofuran is introduced dropwise. The orange-colored solution is stirred for 30 minutes at -70° C. and then 1.28 ml of tetramethylethylenediamine (8.48 mmol) are introduced and then after 10 minutes 5.30 ml of a 1.6M solution of n-butylithium in hexane are introduced. The brown solution is stirred for 2 hours at -78° C. and 1.50 ml of methyl iodide (25 mmol) are added dropwise. After stirring for one hour at -78° C. and then for 10 minutes at 20° C., the reaction mixture is poured into a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and the solvent evaporated off. 0.23 g of the title product is recovered after purification by chromatography on a silica column (eluent: hexane/ethyl acetate; 95:5).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]([CH3:26])([CH3:25])[CH2:9][C:10]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#N)=[CH:14][CH:13]=2)[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1C[O:38]CC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]([CH3:26])([CH3:25])[CH2:9][C:10]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:38])=[CH:14][CH:13]=2)[CH:7]=1
Reactant: C1CCOC1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1ccc(C#N)cc1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1ccc(C=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
To a solution of 79 mg (0.2 mmol) of 4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]benzonitrile in 10 mL of THF was added 11.3 mg (0.3 mmol) of lithium aluminum hydride and the mixture was warmed to reflux. After 18 hours, all the solvent escaped. The reaction was cooled to room temperature, THF was added, and the reaction was quenched with water and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, toluene-EtOAc (95:5)) to leave an oil. A second purification by preparative TLC (silica gel, hexanes-EtOAc (9:1)) afforded 15 mg (18%) of the title compound as an oil which partially solidified.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:20][C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:22])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[C:30](O)(=[O:32])[CH3:31]>C1COCC1.C(Cl)Cl>[F:9][C:7]1[CH:8]=[C:3]([CH2:2][NH:1][C:30](=[O:32])[CH3:31])[C:4]([NH:20][C@H:21]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH3:22])=[N:5][C:6]=1[NH:10][C:11]1[CH:15]=[C:14]([O:16][CH:17]([CH3:18])[CH3:19])[NH:13][N:12]=1
Reactant: CC(=O)O
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(CN)cc2F)n[nH]1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NCc1cc(F)c(Nc2cc(OC(C)C)[nH]n2)nc1N[C@@H](C)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 49 %

Procedure:
(S)-3-(Aminomethyl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)-N6-(5-isopropoxy-1H-pyrazol -3-yl)pyridine-2,6-diamine (Example 18; 0.20 g, 0.49 mmol) and acetic acid loaded TFP resin (1.4 mmol/g loading, 0.49 mmol) were placed in a THF-DCM solution (1:1, 6 ml) at 0° C. The resulting solution was shaken vigorously at 0° C. for 45 min and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.010 g, 49%). 1H NMR (400 MHz, CD3OD) δ 7.37-7.34 (m, 2H), 7.14 (d, J=10.9 Hz, 1H), 7.02-6.98 (m, 2H), 5.25 (s, 1H), 4.96-4.95 (m, 1H), 4.55-4.52 (m, 1H), 4.30 (d, J=14.8 Hz, 1H), 4.21 (d, J=14.8 Hz, 1H), 2.01 (s, 3H), 1.51 (d, J=6.8 Hz, 3H), 1.31 (d, J=6.0 Hz, 6H). MS: Calcd.: 444. Found: [M+H]+ 445.
Reaction SMILES: CCN([C:6]1[CH:11]=[CH:10][C:9]2[C:12]([CH3:17])=[CH:13][C:14]([O:16][C:8]=2[CH:7]=1)=[O:15])CC.C1C(O)=CC=CC=1C.[F:26][C:27]1[CH:32]=[CH:31]C(I)=[CH:29][CH:28]=1.[Br:34]C1C=COC=1>>[F:26][C:27]1[CH:32]=[CH:31][C:17]([C:12]2[C:9]3[C:8](=[CH:7][C:6]([Br:34])=[CH:11][CH:10]=3)[O:16][C:14](=[O:15])[CH:13]=2)=[CH:29][CH:28]=1
Reactant: Brc1ccoc1
Reactant: CCN(CC)c1ccc2c(C)cc(=O)oc2c1
Reactant: Fc1ccc(I)cc1
Solvent: Cc1cccc(O)c1
Product: O=c1cc(-c2ccc(F)cc2)c2ccc(Br)cc2o1

Procedure:
Following the procedures described for Coumarin 1, Steps 1 to 5, but substituting 3-bromophenol for m-cresol and 4-fluoroiodobenzene for 3-bromofuran, the title compound was obtained.
Reaction SMILES: [C:1]([S:5][C:6](=[O:11])[CH2:7][C:8](=[O:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)=[CH:18][CH:17]=1.[Cl-].[Na+]>COCCOC.C(O)(=O)C.O>[C:1]([S:5][C:6](=[O:11])[CH:7]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)=[CH:20][CH:21]=1)[C:8](=[O:10])[CH3:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CC(=O)SC(C)(C)C
Reactant: BrCc1ccc(-n2cccn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: COCCOC
Product: CC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)SC(C)(C)C
Temperature: 15 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
A solution of 3-oxothiobutyric acid S-tert-butyl ester (3.7 g) in 1,2-dimethoxyethane (5.0 mL) was added to a stirred suspension of sodium hydride (60% in oil, 0.92 g) in 1,2-dimethoxyethane (25 mL) at −10° C., and the resulting mixture was warmed to 15° C. over 15 minutes, cooled to −10° C. and then treated dropwise with a mixture of 1-(4-bromomethylphenyl)-1H-pyrazole (5.0 g) in 1,2-dimethoxyethane (20 mL) over a period of 30 minutes. The resulting mixture was warmed to room temperature and then stirred at this temperature for overnight. The mixture was diluted water, pH adjusted to 5 by the addition of glacial acetic acid and then saturated with sodium chloride. The mixture was extracted ethyl acetate and the combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. Purification of the residue purified by column chromatography on silica gel, eluting with a mixture of pentane, dichloromethane and ethyl acetate (1:3:0, 0:1:0 to 0:10:1 by volume) gave title compound as a colourless gum (0.6 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:20]=[C:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:18][N:17]=1)\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:63]1([CH2:68][C@H:69]2[NH:72][C:71](=[O:73])[C@H:70]2[NH2:74])[CH:67]=[N:66][CH:65]=[N:64]1>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[N:63]1([CH2:68][C@@H:69]2[C@H:70]([NH:74][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:8])([CH3:9])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:29])/[C:16]3[N:20]=[C:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[S:18][N:17]=3)[C:71](=[O:73])[NH:72]2)[CH:67]=[N:66][CH:65]=[N:64]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)ns1
Reactant: N[C@@H]1C(=O)N[C@@H]1Cn1cncn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2cncn2)ns1
Reaction time: 0.33 h
Yield: 57.7 %

Procedure:
To a slurry of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)acetic acid (129 mg, 0.299 mmol) in DCM:DMF (1:1, 3 mL) at 0° C. was added DIPEA (157 μL, 0.897 mmol) followed by HATU (136 mg, 0.359 mmol). To the resulting solution, after 20 min, was added a solution of (3S,4R)-4-((1H-1,2,4-triazol-1-yl)methyl)-3-aminoazetidin-2-one (50 mg, 0.299 mmol) in DCM. After 2 h of stirring it was concentrated in vacuo and taken up in EtOAc, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM) to afford the title compound (100 mg, 58%). LCMS: Rt=0.82 min, m/z=580.2 (M+1) Method 2m_acidic.